Nonsurgical treatment of skin cancer with local delivery of bioadhesive nanoparticles

Abstract

Significance One in five individuals in the United States will develop skin cancer over the course of a lifetime, and nonsurgical options are limited. To address this, we developed a bioadhesive nanoparticle (BNP) treatment for long-lasting local drug delivery. Incorporation of the topoisomerase inhibitor camptothecin (CPT) into BNPs enhanced tumor cell uptake, bioadhesion within the tumor microenvironment, and prolonged intratumoral drug retention. Therefore, we investigated BNPs encapsulating CPT as a local, nonsurgical treatment for nodular squamous cell carcinoma (SCC) skin cancers in a mouse model. BNP-CPT treatment facilitated tumor destruction and resolution, and was compatible with local immunotherapy. These findings suggest that BNP delivery of antitumor agents may provide opportunities for nonsurgical treatment of nodular skin cancers like SCC. Keratinocyte-derived carcinomas, including squamous cell carcinoma (SCC), comprise the most common malignancies. Surgical excision is the therapeutic standard but is not always clinically feasible, and currently available alternatives are limited to superficial tumors. To address the need for a nonsurgical treatment for nodular skin cancers like SCC, we developed a bioadhesive nanoparticle (BNP) drug delivery system composed of biodegradable polymer, poly(lactic acid)-hyperbranched polyglycerol (PLA-HPG), encapsulating camptothecin (CPT). Nanoparticles (NPs) of PLA-HPG are nonadhesive NPs (NNPs), which are stealthy in their native state, but we have previously shown that conversion of the vicinal diols of HPG to aldehydes conferred NPs the ability to form strong covalent bonds with amine-rich surfaces. Herein, we show that these BNPs have significantly enhanced binding to SCC tumor cell surfaces and matrix proteins, thereby significantly enhancing the therapeutic efficacy of intratumoral drug delivery. Tumor injection of BNP-CPT resulted in tumor retention of CPT at ∼50% at 10 d postinjection, while CPT was undetectable in NNP-CPT or free (intralipid) CPT-injected tumors at that time. BNP-CPT also significantly reduced tumor burden, with a portion (∼20%) of BNP-CPT–treated established tumors showing histologic cure. Larger, more fully established PDV SCC tumors treated with a combination of BNP-CPT and immunostimulating CpG oligodeoxynucleotides exhibited enhanced survival relative to controls, revealing the potential for BNP delivery to be used along with local tumor immunotherapy. Taken together, these results indicate that percutaneous delivery of a chemotherapeutic agent via BNPs, with or without adjuvant immunostimulation, represents a viable, nonsurgical alternative for treating cutaneous malignancy.